Diastereoselective and enantioselective preparation of nor-mevaldic acid surrogates through desymmetrisation methodology. Enantioselective synthesis of (+) and (-) nor-mevalonic lactones

Article abstract of DOI:10.1016/j.tet.2015.08.010

Solvent-free desymmetrisation of a meso-dialdehyde with chiral alcohols, led to preparation of 4-silyloxy-6-alkyloxytetrahydro-2H-pyran-2-one derivatives with a 96% de. This methodology, which yields the corresponding methyl nor-mevaldates with 99% ee, ha

Full text of DOI:10.1016/j.tet.2015.08.010

Accepted Manuscript
Diastereoselective and enantioselective preparation of nor-mevaldic acid surrogates
through desymmetrisation methodology. Enantioselective synthesis of (+) and (-) nor-
mevalonic lactones
José Manuel Botubol-Ares, María Jesús Durán-Peña, Rosario Hernández-Galán,
Isidro G. Collado, Laurence M. Harwood, Antonio J. Macías-Sánchez
PII:
S0040-4020(15)01187-4
10.1016/j.tet.2015.08.010
TET 27032
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 July 2015
Revised Date: 2 August 2015
Accepted Date: 3 August 2015
Please cite this article as: Botubol-Ares JM, Durán-Peña MJ, Hernández-Galán R, Collado IG, Harwood
LM, Macías-Sánchez AJ, Diastereoselective and enantioselective preparation of nor-mevaldic acid
surrogates through desymmetrisation methodology. Enantioselective synthesis of (+) and (-) nor-
mevalonic lactones, Tetrahedron (2015), doi: 10.1016/j.tet.2015.08.010.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Diastereoselective and enantioselective preparation of Leave this area blank for abstract info.
nor-mevaldic acid surrogates through desymmetrisation
methodology. Enantioselective synthesis of (+) and (-) nor-mevalonic lactones.
a
a
a
a
José Manuel Botubol-Ares , María Jesús Durán-Peña , Rosario Hernández-Galán , Isidro G. Collado
,
b
a
,
Laurence M. Harwood and Antonio J. Macías-Sánchez .∗
a
b
Universidad de Cádiz, Spain. University of Reading, United Kingdom.

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Diastereoselective and enantioselective preparation of nor-mevaldic acid surrogates
through desymmetrisation methodology. Enantioselective synthesis of (+) and (-) nor-
mevalonic lactones.
a
a
a
a
José Manuel Botubol-Ares , María Jesús Durán-Peña , Rosario Hernández-Galán , Isidro G. Collado
,
,
b
a
Laurence M. Harwood and Antonio J. Macías-Sánchez , ∗
a
Departamento de Química Orgánica, Facultad de Ciencias, Campus Universitario Puerto Real, Universidad de Cádiz, Puerto Real, Cádiz,11510, Spain.
Department of Chemistry, University of Reading, Whiteknights, Reading RG6 6AD, United Kingdom
b
Dedicated to Professor Steven V. Ley on the occasion of his 70th birthday
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Solvent-free desymmetrisation of a meso-dialdehyde with chiral alcohols, led to preparation of
4-silyloxy-6-alkyloxytetrahydro-2H-pyran-2-one derivatives with a 96% de. This methodology,
which yields the corresponding methyl nor-mevaldates with 99% ee, has been applied to the
enantioselective synthesis of the (-)-(R) and (+)-(S) nor-mevalonic acid lactones.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Botrytis cinerea
Desymmetrisation
Meso-dialdehyde
nor-Methyl mevaldate
14
15
1
. Introduction
activity, HMG-CoA reductase inhibitors or analogues of
16
17
statins and 6-alkyl-4-hydroxypyran-2-ones with estrogenic
activity. Furthermore, diverse mevalonic lactone analogues with
different substituents in position 4 have been recently synthesized
and reported as inhibitors of the mevalonate pathway in the
Enantioselective desymmetrisation of meso or prochiral
compounds has become a powerful tool in the preparation of
1
enantiomerically pure compounds, using chiral reagents,
2
3
enzymes or catalysts. Symmetrical or achiral precursors may
provide a synthetic advantage by permitting inclusion of a certain
degree of complexity before introducing chirality at the
desymmetrisation step, instead of incorporating chirality at very
early steps of a synthesis.
18
bacterium Streptococcus pneumoniae.
As part of our strategy for the design of antifungal agents
19
against Botrytis and Colletotrichum species, we have recently
reported the preparation of 4-hydroxy-6-(1-
phenylethoxy)tetrahydro-2H-pyran-2-one (2) as selective
a
This approach has been successfully applied to the
antifungal agent against the phytopathogen Botrytis cinerea via
the desymmetrisation reaction of a suitable meso-dialdehyde
4
desymmetrisation of a range of substrates such as dienes, meso-
5
6
anhydrides,
meso-diols
and
meso-dialdehydes.
20,21
precursor 3 with chiral phenylethanol.
Desymmetrisation of meso-dialdehydes has been performed via
7
8
Horner-Wadsworth-Emmons reaction, alkylation, carbonyl-ene
In this paper we extend this methodology to the preparation of
9
a
range of 6-alkyloxy-4-silyloxytetrahydro-2H-pyran-2-ones
cyclization reaction and aldol condensation, either using chiral
10
11
12
reagents, an organometallic catalyst or organocatalysis.
using different chiral alcohols. The use of the dialdehyde 3 as a
building block for the enantioselective preparation of 1,3,5-
trioxygenated substrates related to methyl nor-mevaldate 1, such
as nor-mevalonic acid lactones (-)-(R)-4 and (+)-(S)-5 is also
described (Figure 1). These compounds are of interest for
structure-activity relationship (SAR) studies.
In this respect, the synthetic utility of 1,3,5-trioxygenated
substrates has led to much interest in their enantiocontrolled
13
preparation. For instance, enantiomerically pure methyl nor-
mevaldate 1 has been used as a building block for the synthesis
of bioactive molecules such as β-hydroxyacids with antifungal
—
——
∗
Corresponding author. Tel.: +34-956-012704; fax: +34-956-016193; e-mail: antoniojose.macias@uca.es
1

been shown to lead to better selectivity than the use of dry THF
ACCEPTED MANUSCRIPT
21
for the preparation of lactone (+)-6a, were applied to a series of
commercially available chiral alcohols 10-14, achieving an
optimal 14.7% overall yield and 96% de with (+)-(R) or (-)-(S)-1-
(naphthalen-2-yl)ethanol (Scheme 2 and 3, Table 1, entry 6). Best
yields and de were obtained when 1-arylethanols were used as
chiral auxiliaries (6 and 14), suggesting that efficient
desymmetrisation required not only a stereogenic center directly
attached to the hydroxyl group, but also a large aromatic group
attached to the stereogenic center, as use of (-)-myrtenol resulted
in no asymmetric induction (Table 1, entry 4).
1
2
) 4 Å mol.sieves
R*OH (6, 10-14)
) PCC, CH Cl2
2
3
OTBS
4
OTBS
OTBS
Figure 1. Structures 1-5.
(
R)
(S)
(S)
+
+
6
(S)
(S)
(
R)
2
. Results and discussion
O*R
O
O
O*R
O
O
O*R
O
O
(
(
+)-[6a,12a,14a]
-)-[10a,11a,13a]
(+)-6b
(+)-14b
(+)-[10c,13c]
(-)-[11c,12c]
2
.1. Optimization of desymmetrisation reaction
The absolute stereochemistries of chiral 6-arylalkyloxy-4-
OH
1'
silyloxytetrahydro-2H-pyran-2-ones (+)-6a and (+)-6b were
established unequivocally in previous reports by a combination
of X-ray crystallographic analyses of the structurally related
tetrahydro-2H-pyran-2-ones (+)-7a and (-)-7c, N.O.E. difference
studies and chemical correlation of tetrahydro-2H-pyran-2-ones
1
'
5'
OH
2'
4
'
(
+)-(R)-1-phenyl-ethanol (6)
(-)-(1R,2S,5R)-Isopulegol (10)
(
+)-6a
and
(+)-7a
with
(-)-(R)
methyl
3-(tert-
OH
butyldimethylsilyloxy)-5-oxopentanoate (8) and of tetrahydro-
1
'
2
H-pyran-2-ones (+)-6b and (-)-7c with (+)-(S) methyl 3-(tert-
5'
1'
21
7
'
butyldimethylsilyloxy)-5-oxopentanoate 9 (Scheme 1).
OH
2
'
6
'
(-)-(R)-octan-2-ol (11)
(-)-myrtenol (12)
OH
6'
1'
5
'
1'
OH
5
'
2
'
4
'
7
'
(
-)-(1R,2S,5R)-menthol (13)
(+)-(R)-1-(naphth-2-yl)ethanol (14)
Scheme 2. Solvent-free desymmetrisation of dialdehyde 3
with different chiral alcohols
Table 1. Solvent-free desymmetrisation of dialdehyde 3 with
chiral alcohols 6, 10-14
a
Entry
R*OH
Products (%)
d.e (%)
92
72
60
0
1
2
3
4
5
(+)-(R)-6
(-)-(1R,2S,5R)-10
(-)-(R)-11
(-)-12
(-)-(1R,2S,5R)-13
(+)-(R)-14
6a (12.3), 6b (0.6)
10a (2.5), 10c (0.4)
11a (2.0), 11c (0.5)
12a (2.0), 12c (2.0)
13a (2.0), 13c (0.6)
54
96
6
(+)-14a (14.7), (+)-14b (0.3)
a
Yields obtained after chromatographic purification.
Scheme 1. Chemical correlation of lactones (+)-6a and (+)-7a
with compound (-)-(R)-8 and of lactones (+)-6b and (-)-7c
with (+)-(S)-9
Evaluation of the influence of the chiral alcohol structure on
the diastereoselectivity of the desymmetrisation process was then
20
undertaken. Consequently, solvent-free conditions, which have
2

Stereochemistries of the compounds 10a-14a, 10c-13c and 14b
ACCEPTED MANUSCRIPT
were established by a combination of NOESY studies, analysis of
1
H-NMR coupling constants and comparison with related
lactones 6a, 6b, 7a and 7c, whose absolute stereochemistries
21
have been reported before. For example, compound (+)-14a
presented spectroscopic data closely related to those for
compound 6a, but significantly different to those for compounds
6
b and 7c, while compound 14b presented spectroscopic data
closely related to those for compound 6b. Such correlations and
the N.O.E. enhancement observed between H-6 and H-4 for 14b
allowed us to assign their structures as (4R,6S)-4-((tert-
butyldimethylsilyl)oxy)-6-((R)-1-(naphthalen-2-
yl)ethoxy)tetrahydro-2H-pyran-2-one (+)-14a and (4S,6S)-4-
(
(tert-butyldimethylsilyl)oxy)-6-((R)-1-(naphthalen-2-
1
yl)ethoxy)tetrahydro-2H-pyran-2-one (+)-14b, respectively ( H-
NMR data for compounds 6a-b, 7a, 10a-14a and 14b are
presented in Tables 2 and 3; H-NMR data for compounds 7c and
1
1
1
13
0c-13c in Table 4; C-NMR data for compounds 6a-b, 7a, 10a-
4a, 14b, 7c and 10c-13c in Tables S1-S3 of the supporting
Scheme 3. Preparation of (-)-15a and (-)-15b via solvent-free
desymmetrisation of dialdehyde 3 with (-)-(S)-1-(naphthalen-
information).
2
-yl)ethanol.
1
a
Table 2. H NMR Spectroscopic Data for 6a, 6b, 7a, 14a and 14b
20
20
20
6
a
7a
14a
6b
14b
H
δ (mult, J in Hz)
Position
3
δ
H
(mult, J in Hz)
δ
H
(mult, J in Hz)
δ
H
(mult, J in Hz)
δ
H
(mult, J in Hz)
α: 2.51 (dd, 9.2,
16.8)
α: 2.47 (dd, 5.6, 17.4)
α: 2.51 (dd, 9.2, 17.4)
α: 2.47 (dd, 5.6, 17.2)
β: 2.76 (dd, 4.8, 17.2)
α: 2.50 (dd, 5.6, 17.2)
β: 2.78 (ddd, 0.8, 4.8,
β: 2.69 (ddd, 1.6, 5.6,
17.4)
β: 2.85 (ddd, 1.2, 4.8, 17.2)
β: 2.69 (ddd, 1.8,
1
7.4)
5
.4, 16.8)
4
5
4.33 (m)
4.44 (m)
4.35 (m)
3.98, tt (5.4, 9.2)
3.95 (tt, 5.6, 9.2)
α
1.82 (ddd, 7.7, α: 1.85 (ddd, 7.6, 9.2,
α: 2.13 (dddd, 1.2, 3.8, 4.8, α 1.85 (ddd, 3.6, 7.0, 13.8)
4.0)
α: 1.94 (ddd, 3.6, 5.6, 13.8)
β: 1.85 (ddd, 3.6, 6.8, 13.8)
9.2, 14.0) 14.0)
1
β: 1.98 (dddd, 0.8, 4.0,
β: 2.22 (dddd, 1.8, β: 2.21 (dddd, 1.6, 4.4,
β: 1.95 (ddd, 3.8, 6.8, 14.0) 5.4, 13.8)
4
.4, 5.4, 14.0)
5.6, 14.0)
6
5.25 (dd, 3.6, 5.6)
*0.02 (s)
5.37 (dd, 3.8, 4.8)
5.04 (dd, 4.4, 7.7)
*0.03 (s)
5
.29 (dd, 3.6, 5.4)
5.06 (dd, 4.4, 7.6)
0.01 (s)
Si(CH
3
3
)(CH
3
3
)
)
*0.04 (s)
*0.00 (s)
0.79 (s)
●0
.00 (s)
Si(CH
)(CH
*-0.03 (s)
0.76 (s)
●-
*0.03 (s)
0.07 (s)
0.01 (s)
SiC(CH
3
)
3
0.86 (s)
0
7
7
-
.68 (s)
0.85 (s)
2
3
4
5
6
7
8
’
’
’
’
’
7.36-7.28 (m)
7.36-7.28 (m)
7.36-7.28 (m)
7.36-7.28 (m)
7.36-7.28 (m)
-
7.44-7.36 (m)
7.44-7.36 (m)
7.44-7.36 (m)
7.44-7.36 (m)
7.44-7.36 (m)
-
7.38-7.28 (m)
7.38-7.28 (m)
7.38-7.28 (m)
7.38-7.28 (m)
7.38-7.28 (m)
-
.50-7.42 (m)
.85-7.81 (m)
7.52-7.44 (m)
7.87-7.78 (m)
-
-
-
7
7
7
-
.74 (s)
7.74 (s)
’ and 10’
’ and 9’
.85-7.81 (m)
.50-7.42 (m)
7.87-7.78 (m)
7.52-7.44 (m)
-
-
-
-
CH
3
OCO
-
3.69 (s)
-
ArCH(CH
3
)O
1.46 (d, 6.6)
4.99 (q, 6.6)
-
1.47, d (6.6)
5.08, q (6.6)
1
5
.55 (d, 6.6)
.15 (q, 6.6)
1.56 (d, 6.4)
5.18 (q, 6.4)
ArCHO
5.32 (s)
a
●
Chemical shift values, δ, are in ppm, and the coupling constants, J, are in Hz (parentheses). Interchangeable signals.
3

1
a
Table 3. H NMR Spectroscopic Data for 10a-13a
ACCEPTED MANUSCRIPT
1
0a
11a
12a
(mult, J in Hz)
13a
(mult, J in Hz)
Position
3
δ
H
(mult, J in Hz)
δ
H
(mult, J in Hz)
δ
H
δ
H
α: 2.35 (dd, 6.8, 17.2)
α: 2.48 (dd, 5.6, 17.4)
α: 2.48 (dd, 5.6, 17.6)
α: 2.47 (dd, 6.0, 17.2)
β: 2.77 (ddd, 0.8, 5.6 17.2)
β: 2.76 (ddd, 0.8, 5.0, 17.4)
β: 2.75 (ddd, 0.8, 4.8, 17.6)
β: 2.76 (ddd, 0.8, 5.2, 17.2)
4
5
4
.30 (m)
4.35 (m)
4.34 (m)
4.36 (m)
α: 1.79 (ddd, 4.0, 8.4, 13.6)
β: 2.06-1.91 (m)
α: 2.01-1.90 (m)
β: 2.01-1.90 (m)
α: 1.99-1.90 (m)
β: 1.99-1.90 (m)
α: 1.95-1.85 (m)
β: 1.95-1.85 (m)
6
5
0
0
0
.50 (t, 4.0)
.00 (s)
5.54 (dd, 3.8, 5.0)
0.07 (s)
5.45 (dd, 4.0, 4.8)
0.06 (s)
5.62 (t, 4.2)
0.07 (s)
Si(CH
3
3
)(CH
3
3
)
)
Si(CH
)(CH
.00 (s)
0.07 (s)
0.06 (s)
0.07 (s)
3 3
SiC(CH )
.82 (s)
0.88-0.85 (m)
0.86 (s)
0.89-0.70 (m)
CH(H)O
CH(H)O
-
-
-
-
-
4.15 (dd, 1.4, 12.2)
-
-
-
-
-
4.05 (dd, 1.4, 12.2)
CH(CH
3
3
)O
)O
3.92 (sext, 6.4)
1.13 (d, 6.4)
-
-
CH(CH
α: 1.44-1.36 (m)
β:1.54-1.48 (m)
1
2
’
’
3.68 (dt, 4.2, 10.8)
2.06-1.91 (m)
2.14-2.08 (m)
-
3.64 (dt, 4.4, 10.6)
1.32-1.20 (m)
1.24-1.14 (m)
α: 1.02-0.92 (m)
β: 1.68-1.54 (m)
α: 1.48-1.24 (m)
β: 1.64-1.54 (m)
3
’
1.32-1.20 (m)
5.54 (m)
α: 0.89-0.70 (m)
β: 1.68-1.54 (m)
4
5
6
’
’
’
1.48-1.24 (m)
1.64-1.54 (m)
1.32-1.20 (m)
1.32-1.20 (m)
0.88-0.85 (m)
2.27 (m)
2.14-2.08 (m)
-
1.40-1.28 (m)
α: 0.84-0.78 (m)
β: 2.06-1.91 (m)
α: 0.89-0.70 (m)
β: 2.03-1.96 (m)
α: 1.12 (d, 8.8)
7
’
-
-
-
β: 2.39 (dt, 5.6, 8.8)
C2’C(CH
C2’C(CH
C2’C(CH
3
3
3
)=C(H)(H)
)=C(H)(H)
)=C(H)(H)
1.60 (s)
-
-
-
-
-
-
-
-
-
-
-
-
4.66 (br s)
-
4.67 (br s)
-
C2’CH(CH
3
3
)(CH
3
3
)
)
-
-
-
0.89-0.70 (m)
0.78 (d, 6.8)
-
C2’CH(CH
)(CH
●
C5’-(CH
3
3
)(CH
3
3
)
)
0.81 (s)
●
C5’-(CH
)(CH
-
-
-
1.28 (s)
-
C5’-CH
3
0.89 (d, 6.8)
-
0.88 (d, 6.8)
a
●
Chemical shift values, δ, are in ppm, and the coupling constants, J, are in Hz (parentheses). Interchangeable signals.
4

1
a
Table 4. H NMR Spectroscopic Data for 7c and 10c-13c
ACCEPTED MANUSCRIPT
2
0
7
c
10c
11c
(mult, J in Hz)
12c
(mult, J in Hz)
α: 2.48 (dd, 5.2, α: 2.48 (dd, 5.0,
13c
Position
3
δ
H
(mult, J in Hz)
δ
H
(mult, J in Hz)
δ
H
δ
H
H
δ (mult, J in Hz)
α: 2.49 (dd, 4.8, 17.3)
β: 2.70 (dd, 4.8, 17.3)
α: 2.45 (dd, 5.2, 17.2)
β: 2.69 (dd, 5.2, 17.2)
α: 2.48 (dd, 5.2, 17.2)
β: 2.74 (dd, 5.2, 17.2)
17.2) 17.2)
β: 2.75 (dd, 5.2, β: 2.73 (dd, 5.0,
1
7.2)
17.2)
4
5
6
4
2
.36 (quint, 4.8)
.16 (t, 4.8)
4.29 (quint, 5.2)
1.91-1.87 (m)
5.42 (dd, 4.2, 5.2)
0.05 (s)
4.33 (quint, 5.2)
1.96 (m)
4.34 (quint, 5.2)
1.98-1.94 (m)
5.46 (t, 4.4)
0.06 (s)
4.33 (quint, 5.0)
2.04-1.94 (m)
5.50 (t, 5.0)
0.07 (s)
5
.64 (t, 4.6)
5.52 (dd, 4.6, 5.2)
0.07 (s)
Si(CH
3
3
)(CH
3
3
)
)
●
0
.08 (s)
Si(CH
)(CH
●
0
.07 (s)
0.05 (s)
0.07 (s)
0.06 (s)
0.07 (s)
3 3
SiC(CH )
0
.87 (s)
0.86 (s)
0.90-0.85 (m)
0.86 (s)
0.91-0.80 (m)
CH(H)O
CH(H)O
-
-
-
-
-
-
-
-
-
-
4.20 (dd, 1.6, 12.8)
-
-
-
-
-
-
4.17 (dd, 1.6, 12.8)
CH(CH
3
3
)O
)O
3.83 (sext, 6.0)
-
-
-
CH(CH
1.21 (d, 6.4)
-
ArCHO
5.47 (s)
α: 1.44-1.36 (m)
β: 1.54-1.46 (m)
1
2
3
’
’
’
-
3.60 (dt, 4.4, 10.2)
-
3.45 (dt, 4.8, 10.8)
7.44-7.32 (m)
7.44-7.32 (m)
1.96 (ddd, 3.6, 10.2, 12.8)
1.30-1.24 (m)
2.12-2.08 (m)
5.52 (m)
1.26-1.18 (m)
α: 1.32 (m)
α: 1.05-0.92 (m)
β: 1.65-1.58 (m)
1.30-1.24 (m)
β: 1.66-1.57 (m)
α: 0.88-0.85 (m)
β: 1.66-1.57 (m)
α: 0.91-0.80 (m)
β: 1.65-1.58 (m)
4
5
6
’
’
’
7.44-7.32 (m)
7.44-7.32 (m)
7.44-7.32 (m)
1.30-1.24 (m)
1.30-1.24 (m)
0.90-0.85 (m)
2.27 (m)
1.50-1.41 (m)
2.12-2.08 (m)
-
1.42-1.33 (m)
α: 1.02 (m)
α: 1.05-0.92 (m)
β: 2.22-2.16 (m)
β: 2.14-2.09 (m)
α: 1.15 (d, 8.8)
7
’
-
-
-
-
β: 2.38 (dt, 5.6, 8.8)
C2’C(CH
C2’C(CH
C2’C(CH
3
3
3
)=CH
2
-
1.70 (s)
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
)=C(H)(H)
)=C(H)(H)
-
4.76 (br s)
-
-
4.78 (br s)
-
C2’CH(CH
C2’CH(CH
C2’CH(CH
3
3
3
)(CH
)(CH
)(CH
3
3
3
)
)
)
-
-
0.91-0.80 (m)
-
-
0.77 (d, 7.2)
-
-
2.04-1.94 (m)
§
C5’-(CH
3
3
)(CH
3
3
)
)
-
-
1.26 (s)
-
§
C5’-(CH
)(CH
-
-
0.81 (s)
-
C5’-CH
3
-
0.90 (d, 6.4)
-
-
0.91-0.80 (m)
-
CH COO
3
3.70 (s)
-
-
a
§, ●
Chemical shift values, δ, are in ppm, and the coupling constants, J, are in Hz (parentheses).
Interchangeable signals.
2
5
2
.2. Preparation of nor-mevalonic acid lactones (-)-(R)-4 and
+)-(S)-5
and subsequent lactonization with PTSA
produced the
(
corresponding lactone (-)-(R)-17, that was subsequentially treated
with TBAF/AcOH, affording (R)-nor-mevalonic acid lactone
Desymmetrisation of the
dialdehyde 3 with (-)-(S)-1-(naphthalen-2-yl)ethanol afforded the
corresponding lactone (-)-15a in 14.7% overall yield and 96% de
26
To exemplify the utility of our methodology, and in order to
23,27
((-)-(R)-4) in 70% yield and 79% ee.
18
prepare reference compounds for SAR studies,
enantioselective synthesis of nor-mevalonic acid lactones (-)-(R)-
4
an
13e,22
and (+)-(S)-5
was undertaken from lactones (+)-14a and (-
(
scheme 3); methanolysis of which, reduction with NaBH ,
4
25
)
(
-15a (Scheme 4), which were in turn obtained from dialdehyde 3
Schemes 2 and 3). Treatment of lactone (+)-14a with MeONa
lactonization
to yield (+)-(S)-19 and deprotection with
25
TBAF/AcOH, yielded (S)-nor-mevalonic acid lactone ((+)-(S)-
23
and MeOH at -35ºC yielded (-)-(R)-8 in 52% yield and 99% ee.2
Reduction of (-)-(R)-8 with NaBH at -35ºC to yield (-)-(R)-16
23
5
) in 67% overall yield and 96% ee.
4
4
5

Unless otherwise noted, materials and reagents were obtained
ACCEPTED MANUSCRIPT
4
from commercial suppliers and were used without further
purification. Dichloromethane was freshly distilled from CaH2
and tetrahydrofuran was dried over sodium and benzophenone
and freshly distilled before use. Air- and moisture-sensitive
reactions were performed under an argon atmosphere.
Purification by semi-preparative and analytical HPLC was
performed, respectively, with 250 mm x 10 mm (10µm particles)
and 250 mm x 4 mm (5µm particles) columns using a differential
refractometer detector. Silica gel was used for column
chromatography. TLC analyses were performed on aluminium
plates coated with silica gel with fluorescent indicator (254 nm),
MeONa, MeOH, -35ºC
NaBH , MeOH, -35ºC
(
+)-14a
(-)-(R)-8
9% ee
5
2%
69%
OR
9
OTBS
PTSA, CH Cl2
2
CO CH3
2
HO
O
O
87%
(
-)-(R)-16
R= TBS
(
-)-(R)-17 89% ee
0
.25 mm thick. Enantiomeric excesses (e.e.) were measured by
TBAF,
AcOH/THF
7
0%
GC using a Cyclosil B chiral column (30 m length x 0.25 mm ID,
0
o
.25 µm film thickness), using a FID detector at 320 C, a split
o
R=H; (-)-(R)-4
9% ee
inyector (15:1 ratio) at 250 C, hydrogen as carrier at 10 psi and 1
µL of injection volume. Temperature program is described in the
experimental section for every relevant compound. Specific
rotations were determined with a digital polarimeter. Infrared
spectra were recorded on a FT-IR spectrophotometer and peak
7
NaBH , MeOH, -35ºC
MeONa, MeOH, -35ºC
4
9
(-)-15a
(+)-(S)-
5
0%
72%
-1
1
9
9% ee
position reported in wavenumbers (cm ). H spectra were
recorded on spectrometers operating at 300 and 400 MHz.
13
C
NMR spectra were measured at 75 and 100 MHz with complete
OTBS
OR
proton decoupling. Chemical shifts were referenced to CDCl (δ
3
H
PTSA, CH Cl2
7.25, δ 77.0). NMR assignments were made by combination of
2
C
1
D and 2D techniques. Multiplicities are described using the
2
CO CH3
84%
HO
O
O
following abbreviations: s = singlet, d = doublet, t = triplet, q =
quartet; quint = quintet; sext = sextet; m = multiplet, br = broad.
High-resolution mass spectrometry (HRMS) was recorded with a
double-focusing magnetic sector mass spectrometer in positive
ion mode, or in a QTOF mass spectrometer in positive ion
electrospray mode at 20 V cone voltage.
(
+)-(S)-18
R= TBS
(
+)-(S)-19 96% ee
TBAF,
AcOH/THF
6
7%
R=H; (+)-(S)-5
6% ee
4.2. Procedures
9
4
.2.1. General procedure for the preparation of 6-
alkyloxy-4-(tert-butyldimethylsilyloxy)tetrahydro-
2
H-pyran-2-ones (6a-b, 10a-15a, 14b-15b and 10c-
3c): Desymmetrisation of 3-(tert-
Scheme 4. Preparation of (R) and (S) nor-mevalonic acid
lactones ((-)-(R)-4) and ((+)-(S)-5
1
butyldimethylsilyloxy)pentanedial (3) under
solvent-free conditions followed by PCC oxidation.
The requisite alcohol (See Schemes 2 and 3 of the manuscript)
3
. Conclusions
(
2.9 mmol) was added to
a
mixture 0of 3-(tert-
2
In summary, the optimization of the desymmetrisation of meso
butyldimethylsilyloxy)pentanedial (3) (1 mmol) and 4 Å
molecular sieves (0.5 g for each mmol of 3) under an argon
atmosphere and the mixture stirred for 24h. The slurry was
dialdehyde 3 led to the selective preparation of (+)-(4R,6S)-4-
(tert-butyldimethylsilyl)oxy)-6-((R)-1-(naphthalen-2-
(
yl)ethoxy)tetrahydro-2H-pyran-2-one (14a) and (4S,6R)-4-((tert-
butyldimethylsilyl)oxy)-6-((S)-1-(naphthalen-2-
yl)ethoxy)tetrahydro-2H-pyran-2-one-(15a) in 96% de when
dissolved in CH Cl (20 mL) and added dropwise to a suspension
2 2
of PCC (3.5 mmol) and powdered molecular sieves 4 Å (twice
the weight of the alcohol) in dichloromethane (70 mL) at room
temperature. The reaction was stirred vigorously for 18 h, diethyl
ether was then added (200 mL) and the mixture was stirred for a
further 1 h. The suspension was filtered through a pad of silica
gel and washed through with a further quantity of ether (200
mL). The ether was removed under reduced pressure to give the
crude mixture of tetrahydro-2H-pyran-2-ones which was purified
either
naphthalen-2-yl)ethanol were used under solvent-free conditions
at room temperature. HPLC purification and methanolysis of (+)-
4R,6S,1’R)-(14a) or (-)-(4S,6R,1’S)-(15a) yielded (-)-(R)-methyl
-(tert-butyldimethylsilyloxy)-5-oxopentanoate (-)-(R)-(8) and
(R)-(+)-1-(naphthalen-2-yl)ethanol
or
(S)-(-)-1-
(
(
3
(
(
+)-(S)-methyl 3-(tert-butyldimethylsilyloxy)-5-oxopentanoate
+)-(S)-(9) respectively in 99% ee. Further transformation of
by column chromatography (petroleum ether / Et O, 90:10), to
2
these substrates allowed the enantioselective preparation of the
nor-mevalonic acid lactones (-)-(R)-4 and (+)-(S)-5 (in 42%
overall yield and 79% ee and in 41% overall yield and 96% ee,
respectively).
yield the corresponding tetrahydro-2H-pyran-2-ones in the ratios
and yields shown below and in Table 1 and Schemes 2 and 3 of
the manuscript.
(
-)-(4R(S),6S(R))-4-((tert-butyldimethylsilyl)oxy)-6-
((1R,2S,5R)-5-methyl-2-(prop-1-en-2-
yl)cyclohexyl)oxy)tetrahydro-2H-pyran-2-one (10a). (9.5 mg,
.5%). Colourless oil; HPLC t = 21 min (Petroleum ether : ethyl
(
4
. Experimental section
2
R
20
acetate 93:7; flow = 3.0 mL/min); [α]D -73.7 (c 0.1, CHCl ); IR
3
4
.1. General
(
1
film) υmax 3073, 2932, 2858, 1749, 1644, 1453, 1378, 1228,
-
1 1
145, 1024, 889, 837, 781 cm ; H NMR (CDCl 400 MHz) (see
3,
6

1
3
13
Table 3); C NMR (CDCl 100 MHz) (see Table S2); HRMS
(400 MHz, CDCl ) (see Table 4); C NMR (100 MHz, CDCl )
3 3
+ +
3,
ACCEPTED MANUSCRIPT
+
+
(
CI ): m/z [M+H] , found 383.2608. C H O Si requires
(see Table S3); HRMS (CI ): m/z [M+H] , found 385.2766.
21
39
4
3
83.2618.
C H O Si requires 385.2774.
21
41
4
(
+)-(4S(R),6R(S))-4-((tert-butyldimethylsilyl)oxy)-6-
(+)-(4R,6S)-4-((tert-butyldimethylsilyl)oxy)-6-((R)-1-
(naphthalen-2-yl)ethoxy)tetrahydro-2H-pyran-2-one
(58.8 mg, 14.7%). Colourless oil; HPLC t = 42 min (Petroleum
(
((1R,2S,5R)-5-methyl-2-(prop-1-en-2-
yl)cyclohexyl)oxy)tetrahydro-2H-pyran-2-one (10c). (1.5 mg,
.4%). Colourless oil; HPLC t = 26 min (Petroleum ether : ethyl
acetate 93:7; flow = 3.0 mL/min); [α]D +44.8 (c 0.5, CHCl ); IR
film) υmax 3074, 2928, 2858, 1750, 1647, 1458, 1378, 1256,
(14a).
R
20
0
ether : ethyl acetate 93:7; flow = 3.0 mL/min); [α]D +118.0 (c
1.0, CHCl ); IR (film) υ 3060, 2955, 2858, 1749, 1471, 1382,
R
20
3
3
max
-
1
1
(
1
1231, 1100, 837, 749 cm ; H NMR (400 MHz, CDCl ) (see
3
-
1
1
13
153, 1006, 837, 778 cm ; H NMR (400 MHz, CDCl ) (see
Table 2); C NMR (100 MHz, CDCl ) (see Table S1); HRMS
3
3
13
+
Table 4); C NMR (100 MHz, CDCl ) (see Table S3); HRMS
(ESI-QTOF): m/z [M+Na] , found 423.1968. C H O NaSi
requires 423.1968; [M+H-C H SiOH] , found 269.1161.
3
23 32
4
+
+
+
(
CI ): m/z [M+H] , found 383.2605. C H O Si requires
21
39
4
6 15
3
83.2618.
C H O requires 269.1178.
17 17 3
(-)-(4R(S),6S(R))-4-((tert-butyldimethylsilyl)oxy)-6-((R)-
(+)-(4S,6S)-4-((tert-butyldimethylsilyl)oxy)-6-((R)-1-
octan-2-yloxy)tetrahydro-2H-pyran-2-one (11a). (7.2 mg, 2%).
(naphthalen-2-yl)ethoxy)tetrahydro-2H-pyran-2-one (14b).
Colourless oil; HPLC t = 19 min (Petroleum ether : ethyl 93:7;
(1.2 mg, 0.3%). Colourless oil; HPLC t = 34 min (Petroleum
ether : ethyl acetate 93:7; flow = 3.0 mL/min); [α]D +91.4 (c
R
R
20
20
flow = 3.0 mL/min); [α]D -44.9 (c 0.1, CHCl ); IR (film) υ
3
max
-
1
1
2
930, 2858, 1751, 1464, 1256, 1103, 1008, 837, 778 cm ; H
1.4, CHCl ); IR (film) υ 3056, 2955, 2858, 1749, 1462, 1378,
3
max
13
-1
1
NMR (400 MHz, CDCl ) (see Table 3); C NMR (100 MHz,
1255, 1095, 1027, 837, 778 cm ; H NMR (400 MHz, CDCl )
(see Table 2); C NMR (100 MHz, CDCl ) (see Table S1);
HRMS (ESI-QTOF): m/z [M+Na] , found 423.1968.
C H O NaSi requires 423.1968; [M+H-C H SiOH] , found
3
3
+
+
13
CDCl ) (see Table S2); HRMS (CI ): m/z [M+H] , found
3
3
+
3
59.2625. C H O Si requires 359.2618.
19
39
4
+
23
32
4
6
15
(
-)-(4S(R),6R(S))-4-((tert-butyldimethylsilyl)oxy)-6-((R)-
octan-2-yloxy)tetrahydro-2H-pyran-2-one (11c). (1.8 mg,
.5%). Colourless oil; HPLC t = 27 min (Petroleum ether : ethyl
2
69.1175. C H O requires 269.1178.
17 17 3
0
(-)-(4S,6R)-4-((tert-butyldimethylsilyl)oxy)-6-((S)-1-
(naphthalen-2-yl)ethoxy)tetrahydro-2H-pyran-2-one
(58.7 mg, 14.7%). [α]D -118.0 (c 1.0, CHCl3).
R
20
acetate 93:7; flow = 3.0 mL/min); [α]D -28.3 (c 0.2, CHCl ); IR
(15a).
3
20
(
film) υ 2932, 2857, 1748, 1469, 1256, 1103, 1021, 838, 778
max
-
1
1
13
cm ; H NMR (400 MHz, CDCl ) (see Table 4); C NMR (100
MHz, CDCl ) (see Table S3); HRMS (CI ): m/z [M+H] , found
3
+
+
(-)-(4R,6R)-4-((tert-butyldimethylsilyl)oxy)-6-((S)-1-
3
(
naphthalen-2-yl)ethoxy)tetrahydro-2H-pyran-2-one (15b).
3
59.2625. C H O Si requires 359.2618.
20
19
39
4
(1.3 mg, 0.3%). [α]D -91.4 (c 1.3, CHCl3).
(
+)-(4R(S),6S(R))-4-((tert-butyldimethylsilyl)oxy)-6-
4
.2.2. Preparation of (-)-(R)-Methyl 3-(tert-
(
((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-
yl)methoxy)tetrahydro-2H-pyran-2-one (12a). (7.6 mg, 2%).
Colourless oil; HPLC t = 40 min (Petroleum ether : ethyl acetate
4:6; flow = 0.8 mL/min); [α]D +40.0 (c 0.2, CHCl ); IR
film) υmax 2929, 2858, 1753, 1472, 1383, 1225, 1102, 1030,
38, 778 cm ; H NMR (400 MHz, CDCl ) (see Table 3);
NMR (100 MHz, CDCl ) (see Table S2); HRMS (CI ): m/z
M+H] , found 381.2455. C H O Si requires 381.2461.
butyldimethylsilyloxy)-5-oxopentanoate ((-)-(R)-8).
Sodium methoxide (654.5 mg, 12.12 mmol) was added to a
solution of tetrahydro-2H-pyran-2-one (+)-14a (809.0 mg, 2.02
mmol) in dry MeOH (101 mL) at -35ºC. The reaction was stirred
R
20
9
(
8
3
-
1
1
13
at -35ºC for 24 h, then quenched with saturated NH Cl (110 mL).
4
C
3
+
The mixture was then allowed to warm to room temperature and
diethyl ether (300 mL) was added. The layers were separated and
the aqueous phase was further extracted with diethyl ether (3 x
300 mL). The combined organic layers were washed with brine
(2 x 500 mL), dried over Na SO and the solvent was removed
under reduced pressure to give a crude reaction product, which
was purified by column chromatography (petroleum ether / Et O,
90:10) to give (R)-1-phenylethanol (157.0 mg, 64%) and (-)-(R)–
8 (275.0 mg, 52%, 99% ee) as a colourless oil; [α]D -10.2 (c 0.3,
CHCl ); IR (film) υ 2931, 2898, 2857, 1736, 1438, 1255,
3
+
[
21 37 4
(-)-(4S(R),6R(S))-4-((tert-butyldimethylsilyl)oxy)-6-
(
((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-
yl)methoxy)tetrahydro-2H-pyran-2-one (12c). (7.6 mg, 2%).
Colourless oil; HPLC t = 37 min (Petroleum ether : ethyl acetate
4:6; flow = 0.8 mL/min); [α]D -129.0 (c 0.1, CHCl ); IR
film) υmax 2932, 2858, 1752, 1469, 1369, 1256, 1103, 1023,
38, 777 cm ; H NMR (400 MHz, CDCl ) (see Table 4);
NMR (100 MHz, CDCl ) (see Table S3); HRMS (CI ): m/z
M+H] , found 381.2453. C H O Si requires 381.2461.
2
4
R
2
20
9
(
8
3
20
-
1
1
13
C
3
3
max
+
-1 1
3
1087, 837, 777 cm ; H NMR (400 MHz, CDCl ) δ 9.75 (1H, t, J
= 2.0 Hz), 4.59 (1H, quint, J = 6.2 Hz), 3.63 (3H, s), 2.67-2.62
3
+
[
21
37
4
13
(2H, m), 2.52 (2H, m), 0.80 (9H, s), 0.03 (6H, s); C NMR (100
(-)-(4R(S),6S(R))-4-((tert-butyldimethylsilyl)oxy)-6-
MHz, CDCl ) δ 200.8, 171.1, 64.9, 51.6, 50.8, 42.3, 25.5 (3C),
1
C H O Si requires 245.1209. The enantiomeric excess of 8
3
(
2
1
[
((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)tetrahydro-
H-pyran-2-one (13a). (7.7 mg, 2%). Colourless oil; HPLC t =
6 min (Petroleum ether : ethyl acetate 93:7; flow = 3.0 mL/min);
α]D -67.7 (c 0.15, CHCl ); IR (film) υ
463, 1369, 1255, 1101, 1023, 838, 777 cm ; H NMR (400
MHz, CDCl ) (see Table 3); C NMR (100 MHz, CDCl ) (see
+
+
7.8, -4.9 (2C); HRMS (CI ): m/z [M-CH ] , found 245.1199.
3
R
11
21
4
20
could be determined by chiral gas chromatography, using the
o
2929, 2858, 1753,
3
max
-
1
1
general conditions stated above; isocratic 80 C. t (min) : 251.36.
R
1
13
3
3
4.2.3. Preparation of (+)-(S)-Methyl 3-(tert-
butyldimethylsilyloxy)-5-oxopentanoate ((+)-(S)-9).
(-)-15a (660.0 mg, 1.65 mmol) was converted into (+)-(S)-
Methyl 3-(tert-butyldimethylsilyloxy)-5-oxopentanoate ((+)-(S)-
9
described above for the synthesis of (-)-(R)-8 from (+)-14a.
Colourless oil; [α]D +10.2 (c 0.25, CHCl ). The enantiomeric
excess of 9 could be determined by chiral gas chromatography,
using the general conditions stated above; isocratic 80 C. t (min)
+
+
Table S2); HRMS (CI ): m/z [M+H] , found 385.2764.
C H O Si requires 385.2774.
2
1
41
4
(
+)-(4S(R),6R(S))-4-((tert-butyldimethylsilyl)oxy)-6-
((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)tetrahydro-
H-pyran-2-one (13c). (2.3 mg, 0.6%). Colourless oil; HPLC tR
21 min (Petroleum ether : ethyl acetate 93:7; flow = 3.0
) (220.0 mg, 50%, 99% ee) following the methodology
(
2
=
20
3
20
mL/min); [α]D +21.1 (c 0.1, CHCl ); IR (film) υ 2930, 2859,
752, 1464, 1369, 1253, 1104, 1013, 837, 778 cm ; H NMR
3
max
o
-
1
1
R
1
:
256.19.
7

chiral gas chromatography, using the general conditions stated
ACCEPTED MANUSCRIPT
o
above; isocratic 100 C. t (min) : 244.97 (minor), 249.28 (major).
R
4
.2.4. Preparation of (-)-(R)-Methyl 3-(tert-
butyldimethylsilyloxy)-5-hydroxypentanoate ((R)-
6).
Sodium borohydride (28.5 mg, 0.75 mmol) was added to a
4.2.7. Preparation of (+)-(S)-4-((tert-
butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-one
1
(
(S)-19).
solution of (R)-8 (153.7 mg, 0.59 mmol) in dry MeOH (101 mL)
(+)-(S)-Methyl
3-(tert-butyldimethylsilyloxy)-5-
at -35ºC under an argon atmosphere. The reaction was stirred at -
hydroxypentanoate ((S)-18) (48.0 mg, 0.18 mmol) was converted
into (+)-(S)-4-((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-
2-one ((S)-19) (35.6 mg, 84%, 96% ee) following the
methodology described above for the synthesis of (R)-17 from
3
5ºC for 24 h, adding two supplementary portions of NaBH (15
4
mg each portion). Then 1M HCl was added until pH 7 (8 mL)
and the reaction was allowed to warm to room temperature.
Solvent was removed under reduced pressure and ethyl acetate
20
(R)-16. Colourless oil; [α]D +2.9 (c 0.3, CHCl ). The
3
(50 mL) and brine (15 mL) were added. The layers were
enantiomeric excess of 19 could be determined by chiral gas
separated and the aqueous layer was further extracted with ethyl
acetate (3 x 50 mL). The combined organic layers were washed
with brine (100 mL), dried over Na SO , filtered and the solvent
was removed under reduced pressure to give the crude reaction
product which was purified by column chromatography
chromatography, using the general conditions stated above;
o
isocratic 100 C. t (min) : 238.88 (major), 242.38 (minor).
R
2
4
4
2
.2.8. Preparation of (-)-(R)-4-hydroxytetrahydro-
H-pyran-2-one ((R)-4).
(-)-(R)-4-((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-
(
6
petroleum ether / EtOAc, 90:10) to give (R)–16 (106.7 mg,
9%) and (R)-4-((tert-butyldimethylsilyl)oxy)tetrahydro-2H-
pyran-2-one (R)-17 (12.4 mg, 9%). Data for (R)-16: Colourless
one ((R)-17) (27.4 mg, 0.12 mmol) was converted into (-)-(R)-4-
hydroxytetrahydro-2H-pyran-2-one ((R)-4) (9.7 mg, 70%, 79%
2
0
20
ee) following the methodology described in the literature.
oil; [α]D -2.0 (c 3.1, CHCl ); IR (film) υ
1
3422, 2930, 1741,
3
max
20
-
1
1
Colourless oil; [α]D -3.1 (c 0.34, CHCl ); IR (film) υ
3422,
max
3
438, 1257, 1161, 1026, 837, 777 cm ; H NMR (400 MHz,
-
1
1
2
926, 2875, 1719, 1458, 1383, 1261, 1079 cm ; H NMR (400
CDCl ) δ 4.30 (1H, ddt, J = 12.4, 6.4, 4.8 Hz), 3.76-3.66 (2H, m),
3
MHz, CDCl ) δ 4.57 (1H, ddd, J = 11.4, 8.0, 4.0 Hz), 4.34 (1H,
3
3
1
.64 (3H, s), 2.53 (2H, dd, J = 17.6, 6.4 Hz), 2.47 (2H, dd, J =
quint, J = 5.2 Hz), 4.28 (1H, ddd, J = 11.4, 6.4, 4.8 Hz), 2.82
(1H, dd, J = 17.6, 5.2 Hz), 2.58 (1H, ddd, J = 17.6, 5.2, 1.0 Hz),
7.6, 6.4 Hz), 2.42 (s, OH), 1.85-1.65 (2H, m), 0.84 (9H, s), 0.07
13
(
5
3H, s), 0.04 (3H, s); C NMR (100 MHz, CDCl ) δ 171.8, 68.0,
3
+
13
2.12 (1H, m), 1.89 (1H, m), 1.64 (s, OH); C NMR (100 MHz,
9.4, 51.5, 42.1, 38.9, 25.6 (3C), 17.8, -4.8, -4.9; HRMS (CI ):
+
+
+
CDCl ) δ 170.0, 65.2, 63.4, 39.4, 31.0; HRMS (CI ): m/z [M] ,
3
m/z [M-C(CH ) ] , found 205.0899. C H O Si requires
3
3
8
17
4
found 116.0475. Calcd for C H O 116.0473. The enantiomeric
5
8
3
2
05.0896.
excess of 4 could be determined by chiral gas chromatography,
o
4
.2.5. Preparation of (+)-(S)-Methyl 3-(tert-
using the general conditions stated above; isocratic 100 C. tR
butyldimethylsilyloxy)-5-hydroxypentanoate ((S)-
8).
+)-(S)-Methyl
oxopentanoate ((S)-9) (110.0 mg, 0.42 mmol) was converted into
+)-(S)-Methyl 3-(tert-butyldimethylsilyloxy)-5-
hydroxypentanoate ((S)-18) (85.0 mg, 72%) and (S)-19 (7.0 mg,
%) following the methodology described above for the synthesis
(
min) : 208.23 (minor), 211.67 (major).
1
4
2
.2.9. Preparation of (+)-(S)-4-hydroxytetrahydro-
H-pyran-2-one ((S)-5).
(
3-(tert-butyldimethylsilyloxy)-5-
(+)-(S)-4-((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-
(
2
4
-one ((S)-19) (31.1 mg, 0.14 mmol) was converted into (+)-(S)-
-hydroxytetrahydro-2H-pyran-2-one ((S)-5) (10.5 mg, 67%,
7
2
0
20
96% ee) following the methodology described in the literature.
Colourless oil; [α]D +3.6 (c 0.2, CHCl ). The enantiomeric
excess of 5 could be determined by chiral gas chromatography,
using the general conditions stated above; isocratic 100 C. tR
of (R)-16 from (R)-8. Data for (S)-18: Colourless oil; [α]D +2.0
c 0.2, CHCl3).
20
3
(
o
4
.2.6. Preparation of (-)-(R)-4-((tert-
butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-one
(min) : 204.26 (major), 217.71 (minor).
(
(R)-17).
p-toluenesulfonic acid monohydrate (PTSA) (1.8 mg, 0.01
Acknowledgments
mmol) was added to a solution of (-)-(R)-Methyl 3-(tert-
butyldimethylsilyloxy)-5-hydroxypentanoate ((R)-16) (38.0 mg,
This research was supported by grants from MINECO
(AGL2012-39798-C02-01) and from the Junta de Andalucía
(P07-FQM-02689) (Spain). A. J. M. S. gratefully acknowledges a
RSC research fund grant (UK). J. M. B. thanks Junta de
Andalucía for Research Fellowship. Use of NMR and mass
spectrometry (QTOF) facilities at Servicio Centralizado de
Ciencia y Tecnología (SCCYT) of the University of Cádiz is
acknowledged.
0
.15 mmol) in dry CH Cl (2.3 mL) at room temperature. When
2 2
TLC analysis indicated the completion of the reaction (1 h),
saturated NaHCO was added (3 mL) and the mixture was stirred
3
for a further 15 min. The aqueous phase was then extracted with
ethyl acetate (3 x 25 mL), the combined organic layers were
washed with brine (50 mL), dried over Na SO and filtered.
2
4
Evaporation of the solvent gave the crude product that was
purified by silica gel column chromatography (petroleum ether /
EtOAc, 90:10), to yield (R)-17 (28.9 mg, 87%, 89% ee).
References and notes
2
0
Colourless oil; [α]D -2.8 (c 0.1, CHCl ); IR (film) υ
2
2930,
3
max
-
1
1
857, 1739, 1472, 1260, 1161, 1085, 837, 778 cm ; H NMR
1. (a) Rovis T. In NewFrontiersin Asymmetric Catalysis; Mikami, K
and Lautens, M. Eds.; Wiley: Hoboken, 2006, pp 275-311. (b)
Anstiss, M.; Holland, J. M.; Nelson, A.; Titchmarsh, J. R. Synlett
(
300 MHz, CDCl ) δ 4.56 (1H, ddd, J = 11.2, 9.6, 3.9 Hz), 4.30-
3
4
1
0
6
.22 (2H, m), 2.69 (1H, dd, J = 17.4, 5.0 Hz), 2.52 (1H, dd, J =
2
003, 8, 1213. (c) Willis, M. C. J. Chem. Soc. Perkin Trans. 1
7.4, 4.2 Hz), 2.05-1.94 (1H, m), 1.83-1.73 (1H, m), 0.86 (9H, s),
1
3
1999, 1765. (d) Ward, R. S. Chem. Soc. Rev. 1990, 19, 1.
.06 (3H, s), 0.05 (3H, s); C NMR (75 MHz, CDCl ) δ 170.0,
3
2
.
(a) Garcia-Urdiales, E.; Alfonso, I.; Gotor, V. Chem. Rev. 2011,
+
5.3, 63.9, 40.0, 31.3, 25.6 (3C), 18.0, -4.8, -4.9; HRMS (CI ):
1
11(5), PR110. (b) Garcia-Urdiales, E.; Alfonso, I.; Gotor, V.
+
m/z [M-C(CH ) ] , found 173.0645. C H O Si requires
Chem. Rev. 2005, 105(1), 313.
3
3
7
13
3
3
4
5
.
.
.
Hoffmann, R. Angew. Chem. Int. Ed. 2003, 42, 1096.
Nakahara, K.; Fujioka, H. Symmetry, 2010, 2(2), 437.
Atodiresei, I.; Schiffers, I.; Bolm, C. Chem. Rev. 2007, 107, 5683.
1
73.0634. The enantiomeric excess of 17 could be determined by
8

6
7
.
.
Rendler, S.; Oestreich, M. Angew. Chem. Int. Ed. 2008, 47, 248.
ACCEPTED MANUSCRIPT
(a) Strand, D.; Norrby, P.; Rein, T. J. Org. Chem. 2006, 71, 1879.
b) Vares, L.; Rein, T. Org. Lett. 2000, 2, 2611. (c) Tullis, J. S.;
Vares, L.; Kann, N.; Norrby, P.; Rein, T. J. Org. Chem. 1998, 63,
284. (d) Kann, N.; Rein, T. J. Org. Chem. 1993, 58, 3802.
(a) Bouzbouz, S.; Popkin, M. E.; Cossy, J. Org. Lett. 2000, 2(22),
449. (b) Takemoto, Y.; Baba, Y.; Honda, A.; Nakao, S.;
Noguchi, I.; Iwata, C.; Tanaka, T.; Ibuka, T. Tetrahedron 1998,
4, 15567. (c) Takemoto, Y.; Baba, Y.; Noguchi, I.; Iwata, C.
(
8
8
.
.
3
5
Tetrahedron Lett. 1996, 37(19), 3345. (d) Wang, Z.; Deschênes,
D. J. Am. Chem. Soc. 1992, 114, 1090. (e) Roush, W. R.; Park, J.
C. Tetrahedron Lett. 1990, 31, 4707.
Grachan, M. L.; Tudge, M. T.; Jacobsen, E. N. Angew. Chem. Int.
Ed. 2008, 47, 1469.
9
1
0. (a) Oppolzer, W.; Walther, E.; Pérez Balado, C.; De Brabander, J.
Tetrahedron Lett. 1997, 38, 809. (b) Oppolzer, W.; De Brabander,
J.; Walther, E.; Bernardinelli, G. Tetrahedron Lett. 1995, 36,
4
2
413. (c) Ziegler, F. E.; Becker, M. R. J. Org. Chem. 1990, 55,
800.
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1. Dodd, K.; Morton, D.; Worden, S.; Narquizian, R.; Nelson, A.
Chem. Eur. J. 2007. 13, 5857.
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1
2. Mans, D. M.; Pearson, W. H. Org. Lett. 2004, 6(19), 3305.
3. (a) Rosen, T.; Heathcock, C. H. J. Am. Chem. Soc. 1985, 107.
3
5
731. (b) Theisen, P. D.; Heathcock, C. H. J. Org. Chem. 1988,
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H. Tetrahedron Lett. 1994, 35, 1825. (d) Kumar, A.; Dittmer, D.
C. J. Org. Chem. 1994, 59, 4760. (e) Loubinoux, B.; Sinnes, J-L.;
O’Sullivan, A. C.; Winkler, T. Tetrahedron 1995, 51, 3549-3558.
4. (a) Beuerle, T.; Schreier, P.; Brunerie, P.; Bicchi, C.; Schwab, W.
Phytochemistry 1996, 43, 145. (b) Sjögren, J.; Magnusson, J.;
Broberg, A.; Schnürer, J.; Kenne, L. Appl. Environ. Microbiol.
1
2
003, 69, 7554.
1
1
5. Carosi, L.; Hall, D. Can. J. Chem. 2009, 87, 650 and references
included therein.
6. Stokker, G. E.; Alberts, A. W.; Anderson, P. S.; Cragoe, E. J.;
Deana, A. A.; Gilfillan, J. L.; Hirshfield, J.; Holtz, W. J.;
Hoffman, W. F.; Huff, J. W.; Lee, T. J.; Novello, F. C.; Prugh, J.
D.; Rooney, C. S.; Smith, R. L.; Willard, A. K. J. Med. Chem.
1
986, 29, 170.
1
7. Huang, C-J.; Wang, S-C. Kuo, Y-H. Hong, Y-H. Lin, B-F. Hsu, C.
U. S. Patent, US 20100125102 A1, 2010; Chem. Abstr. 2010, 152,
5
61033.
1
1
2
8. Kudoh, T.; Park, C. S.; Lefurgy, S. T.; Sun, M.; Michels, T.; Leyh,
T. S.; Silverman, R. Bioorg. Med. Chem. 2010, 18, 1124.
9. Collado, I. G.; Sanchez, A. J. M.; Hanson, J. R. Nat. Prod. Rep.
2
007, 24, 674.
0. Botubol-Ares, J. M.; Durán-Peña, M. J.; Hernández-Galán, R.;
Collado, I. G.; Harwood, L. M.; Macías-Sánchez, A. J. Bioorg.
Med. Chem. 2015, 23, 6325.
2
2
1. Buckley, S. L. J.; Drew, M. G. B.; Harwood, L. M.; Macías-
Sánchez, A. J. Tetrahedron Lett. 2002, 43, 3593.
2. (a) Miyashita, M.; Suzuki, T.; Hoshino, M.; Yoshikoshi, A.
Tetrahedron 1993, 53(37), 12469. (b) Kitanosono, T.; Xu, P.;
Kobayashi, S. Chem. Asian J. 2014, 9, 179.
2
2
3. Determined by chiral GC.
4. Novák, L.; Rohály, J.; Poppe, L.; Hornyánszky, G.; Kolonits, P.;
Zelei, I.; Fehér, I.; Fekete, J.; Szabó, E.; Záhorszky, U.; Jávor, A.;
Szántay, C. Liebigs Ann. Chem. 1992, 145.
2
5. See, for instance: Yu, X. M.; Han, H.; Blagg, B. S. J. J. Org.
Chem. 2005, 70, 5599.
2
2
6. Smith, A. B.; Ott, G. R. J. Am. Chem. Soc. 1996, 118, 13095.
7. Lower enantiomeric excesses, particularly for (-)-(R)-17 and (-)-
(R)-4, can be attributed to an incomplete removal of PTSA during
the work-up.
Supplementary Material
1
3
C spectroscopic data for compounds 6a-b, 7a, 10a-14a, 14b,
1
13
7
c and 10c-13c together with H and C-NMR spectra for
compounds 4, 6a-b, 7a, 7c, 8, 10a-14a, 10c-13c, 14b, 16-17,
selected NOESY1D for compounds 11a, 11c, 14a and 14b, and
chiral GC chromatograms for compounds 4-5, 8-9, 17, and 19.
9

ACCEPTED MANUSCRIPT
Supporting Information
Diastereoselective and enantioselective preparation of nor-mevaldic acid
surrogates through desymmetrisation methodology. Enantioselective
synthesis of (+) and (-) nor-mevalonic lactones.
†
†
†
José Manuel Botubol, María Jesús Durán-Peña, Rosario Hernández-Galán, Isidro G.
†
‡
†*
Collado, Laurence M. Harwood and Antonio J. Macías-Sánchez
†Departamento de Química Orgánica, Facultad de Ciencias Campus Universitario Puerto
Real, Universidad de Cádiz, 11510, Puerto Real, Cádiz, Spain
‡Department of Chemistry, University of Reading, Whiteknights, Reading RG6 6AD (UK)
E-mail: antoniojose.macias@uca.es
Table of contents:
1
3
Part A : C NMR data……...…………………..……....………………..S2-4
1
13
Part B : H and C-NMR spectra………………...……………..……...S5-32
Part C: Selected NOESY1D spectra for compounds
1
1a, 11c, 14a and 14b......................................................................S33-36
Part D: Chiral GC chromatograms for comps. 4, 5, 8, 9, 17, and 19….S37-47
S-1ꢀ

ACCEPTED MANUSCRIPT
PART A : NMR data
1
3
Table S1. C NMR data (100 MHz, CDCl
3
) for 6a, 7a, 14a, 6b and 14b
¡
Error!
¡Error!
¡Error!
6
a
7a
6b
14b
1
3
Marcador
Marcador
Marcador
Carbon/δ C
14a
no definido.
no definido.
no definido.
2
3
4
5
6
169.7 s
39.9 t
168.8 s
40.0 t
169.7 s
40.0 t
169.5 s
40.1 t
169.5 s
40.1 t
62.5 d
62.4 d
62.5 d
62.6 d
62.6 d
37.0 t
36.7 t
37.1 t
38.7 t
38.7 t
97.9 d
98.0 d
97.9 d
97.9 d
97.7 d
●- 5.0 q
●- 4.9 q
25.5 q
●-5.0 q
●-4.8 q
25.5 q
●- 5.1 q
●- 4.9 q
25.4 q
●- 4.8 q
●- 4.7 q
25.6 q
●- 4.8 q
●- 4.8 q
25.6 q
Si(CH
Si(CH
3
3
)(CH
)(CH
3
)
)
3
SiC(CH
SiC(CH
3
3
)
3
3
)
17.8 s
17.8 s
17.7 s
17.9 s
17.9 s
ArCH(R
1
)O
75.8 d
78.1 d
75.9 d
75.8 d
75.9 d
1’
2’
3’
4’
5’
141.9 s
*126.5 d
*128.6 d
128.0 d
*128.6 d
134.8 s
*128.8 d
*127.6 d
129.2 d
*127.6 d
139.0 s
++126.2 d
§128.7 d
*133.2 s
*133.2 s
142.0 s
*126.6 d
*128.7 d
128.0 d
*128.7 d
139.0 s
++126.4 d
§128.8 d
*133.2 s
*133.1 s
++1
26.2 d
*126.5 d
*128.8 d
++126.3 d
*126.6 d
6’
-
-
-
-
§127.9 d
++126.1 d
++123.8 d
§127.6 d
-
§127.9 d
++126.2 d
++123.9 d
§127.7d
-
7
8
9
’
’
’
-
-
-
-
-
-
10’
-
-
CH
3
3
OCO
OCO
-
-
170.1 s
52.5 q
-
-
-
CH
-
-
ArCH(CH
3
)O
23.8 q
23.6 q
24.0 q
23.7 q
Chemical shift values, δ, are in ppm, and the coupling constants, J, are in Hz (parentheses) (*, ++, §, ●)
Interchangeable signals.
S-2ꢀ

ACCEPTED MANUSCRIPT
1
3
Table S2. C NMR data (100 MHz, CDCl ) for 10a-13a.
3
1
3
Carbon/δ C
10a
169.9 s
40.4 t
62.3 d
37.7 t
95.7 d
11a
169.7 s
40.1 t
62.6 d
37.6 t
97.9 d
12a
169.7 s
40.0 t
62.5 d
37.0 t
99.0 d
13a
169.6 s
40.1 t
62.6 d
37.7 t
96.6 d
2
3
4
5
6
●
●
●
●
Si(CH
3
3
)(CH
3
3
)
)
-4.9 q
-4.9 q
-4.9 q
-4.9 q
●
●
●
●
Si(CH
)(CH
-4.9 q
-4.8 q
-4.9 q
-4.8 q
SiC(CH
SiC(CH
3
)
3
3
25.7 q
25.7 q
17.9 s
-
25.6 q
25.7 q
3
)
18.0 s
17.9 s
18.0 s
CH
2
O
-
71.6 t
-
CH(CH
CH(CH
3
)O
)O
-
73.9 d
19.0 q
37.0 t
-
-
3
-
75.1 d
51.6 d
30.4 t
34.2 t
31.2 d
39.0 t
-
-
-
1
2
3
4
5
6
7
’
’
’
’
’
’
’
43.2 d
76.2 d
47.8 d
23.2 t
34.4 t
31.3 d
39.6 t
-
§
22.6 t
143.6 s
§
25.4 t
121.9 d
§
29.2 t
31.3 t
§
31.8 t
40.7 d
14.1 q
38.1 s
-
-
-
-
-
-
-
-
-
-
31.3 t
C2’C(CH
C2’C(CH
C2’C(CH
3
3
3
)=CH
)=CH
)=CH
2
2
2
19.0 q
147.1 s
111.5 t
-
-
-
-
-
-
-
-
-
-
C2’CH(CH
C2’CH(CH
C2’CH(CH
3
3
3
)(CH
3
3
3
)
)
)
25.7 d
20.9 q
15.7 q
-
)(CH
)(CH
-
-
§
C5’-CH
3
3
(CH
3
3
)
)
-
21.0 q
§
C5’-CH
(CH
-
26.1 q
-
C5’-CH
3
22.2 q
-
22.3 q
Chemical shift values, δ, are in ppm. ( , ●) Interchangeable signals.
§
S-3ꢀ

ACCEPTED MANUSCRIPT
1
3
Table S3. C NMR data (100 MHz, CDCl ) for 7c and 10c-13c.
3
1
3
Carbon/δ C
7c
10c
11c
12c
13c
2
3
4
168.9 s
39.9 t
169.8 s
39.8 t
169.7 s
39.9 t
169.6 s
40.0 t
169.8 s
39.9 t
62.4 d
62.6 d
62.6 d
62.5 d
62.6 d
3
6.7 t
37.0 t
37.4 t
37.0 t
37.3 t
5
6
99.1 d
●-4.9
●-4.9
102.0 d
●-5.0 q
●-4.9 q
100.5 d
●-4.9
●-4.8
99.4 d
●-4.9 q
●-4.9 q
25.7 q
18.0 s
71.5 t
-
102.4 d
●-4.9 q
●-4.8 q
Si(CH
Si(CH
3
3
)(CH
)(CH
3
)
)
3
SiC(CH
SiC(CH
3
3
)
3
3
25.6 q
25.6 q
25.6 q
25.6 q
)
17.9 s
17.9 s
17.9 s
17.9 s
1
2
C(R )(R )O
77.3 d
-
-
-
CH(CH
CH(CH
3
3
)O
)O
-
-
76.9 d
-
-
-
21.5 q
-
-
1
2
3
4
5
6
7
’
’
’
’
’
’
’
135.3 s
§128.6 d
§127.3 d
81.1 d
36.4 t
§22.6 t
§25.3 t
§29.3 t
31.5 t
143.8 s
121.3 d
31.2 t
40.6 d
37.9 s
43.6 d
-
82.1 d
51.9 d
48.6 d
30.3 t
23.2 t
128.9 d
§128.6 d
§127.3 d
34.0 t
34.2 t
31.6 d
§31.8 t
31.7 d
42.5 t
14.1 q
42.9 t
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
C2’C(CH
C2’C(CH
C2’C(CH
3
3
3
)=CH
)=CH
)=CH
2
2
2
-
20.5 q
-
-
146.9 s
-
-
-
111.8 t
-
-
C2’CH(CH
C2’CH(CH
C2’CH(CH
3
3
3
)(CH
3
)
)
)
-
-
-
25.9 d
)(CH
)(CH
3
3
-
-
-
21.0 q
-
-
-
16.3 q
-
-
§21.3 q
§26.1 q
-
C5’-(CH
C5’-(CH
3
)(CH
)(CH
3
)
3
3
)
-
-
-
C5’-CH
3
-
22.0 q
-
-
22.1 q
CH
3
3
OCO
OCO
170.7 s
52.4 q
-
-
-
-
-
CH
Chemical shift values, δ, are in ppm. (§, ●) Interchangeable signals.
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13
PART B : H AND C-NMR SPECTRA
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